Chapter 2 Gene Environment Interactions, Phenotypic Changes, and Human Health

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1 Chapter 2 Gene Environment Interactions, Phenotypic Changes, and Human Health Rosemarie G. Ramos and Kenneth Olden Abstract The contribution of the environment to the development of chronic disease has historically been documented. As early as 1775, scrotal and nasal cancer was observed among chimney sweepers in London, England by British physician, Percival Potts. His hypothesis was that these cancers were induced by cumulative environmental exposure to chimney soot as they worked. The discipline of cancer epidemiology has continued in the tradition of Dr. Potts. The purpose of this discipline has not been to prove a cause-effect relationship between exposure and development of disease but to identify the common thread of exposures. Today, cancer epidemiology incorporates various scientific disciplines (i.e., risk assessment, toxicology, cellular and molecular biology) to quantify the dose-response relationship between an individual and suspect environmental factor. With the completion of the Human Genome Project in 2003, we now know that individual genetic variability plays a significant role in modifying the effect of environmental exposures on disease development. Additionally, the utility of assessing the individual s genetic variability is invaluable in estimating the degree of severity at time of diagnosis as well as the risk of metastasis and other complications. This chapter explores the relationship of gene environment interactions in cancer from an environmental epidemiology and public health perspective. Keywords Gene environment interactions Cancer Environmental epidemiology Public health perspective R.G. Ramos (B) Laboratory of Molecular Carcinogenesis, Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA ramosr@niehs.nih.gov D. Roy, M.T. Dorak (eds.), Environmental Factors, Genes, and the Development of Human Cancers, DOI / _2, C Springer Science+Business Media, LLC

2 12 R.G. Ramos and K. Olden 2.1 History of the Relationship Between Genes, Environment, and Human Disease The belief that the environment plays a critical role in human disease development dates back to the 1700s. As early as 1775, Dr. Percival Potts reported that the incidence of scrotal cancer among chimney sweeps was linked to their occupational exposure to soot (Harrison, 2004). In 1854, Dr. John Snow documented that a cholera outbreak in the Soho area of London, England could be traced to a specific public water source; the Broad Street Pump (Newsom, 2006). Through the use of statistics and geographical maps (i.e., geographic epidemiology) showing the neighborhood-specific distribution of disease incidence, he was able to convince public officials to remove this environmental hazard and eventually the incidence of cholera diminished. In more modern times, environmental exposures that are associated with human disease include poor air quality, hazardous chemicals in the occupational setting, agricultural pesticides, and personal lifestyle choices (i.e., smoking, alcohol use, diet). However, it has become apparent that not every individual who is exposed to a particular environmental factor (i.e., cigarettes, heavy drinking, a high-fat diet) will develop the associated disease (i.e., lung, liver, or pancreatic cancer, respectively). Furthermore, diseases with an environmentallyrelated etiology are no longer restricted to cancer and now include asthma, cardiovascular disease, and obesity (Bernal-Pacheco and Roman, 2007; Grarup and Andersen, 2007, Newbold et al., 2007; Rundle et al., 2007; Heinrich et al., 2008). The variability of an individual s response to environmental stimuli was originally thought to have been a function of the dose of the environmental stimuli and the route of exposure. More recently, these risk assessments have expanded the definition of environmental stimuli to include social and economic risk factors (i.e., educational attainment, housing characteristics). In addition to disease development being the response, researchers now examine the incidence of health complications and reduction in quality of life. With the evolution of genomics, individual variability in response to environmental stimuli is better understood. The completion of the Human Genome Project has resulted in considering one s genotype as an additional risk factor in dose-response risk assessments. Additionally, the Human Genome Project has given rise to two emerging and exciting fields; molecular epidemiology and bioinformatics. Molecular epidemiology is a multi-disciplinary field that seeks to characterize the prevalence of functional biomarkers among diseased and non-diseased populations (Khoury et al., 2004, 2005). With the emergence of this discipline, the ability to quantify the relationship between environmental exposures and diseasespecific mechanisms is now possible. Thus, molecular epidemiology allows a novel approach to improve population health by identifying the patterns of variability that increase the risk for disease morbidity and mortality. Bioinformatics is a field that was developed in response to the need of molecular biologists who required the creation and management of large datasets containing nucleotide and amino sequences as well as protein domains and structures that could be queried and one

3 2 Gene Environment Interactions, Phenotypic Changes, and Human Health 13 where updates could be routinely performed (National Center for Biotechnology Information, 2004). Thus, the field of bioinformatics was well-suited to assume the task of merging the information from molecular biology and epidemiology studies. Ultimately, the powerful analytical tools of molecular epidemiology and bioinformatics will enable biomedical researchers to assess the contribution from multiple sources of risk (i.e., genes, social/physical environment) towards normal and not-so-normal physiological processes. 2.2 Health Disparities and Genetics Historically, disproportionate rates of disease and mortality have been attributed to the lack of adequate economic and social safety nets. The aforementioned Broad Street Pump event in 1850s London, England was highly influenced by the concentration of inadequate housing and the poor in the Pump s immediate vicinity (Newsom, 2006). When the pump was closed, the cholera epidemic virtually disappeared. Other significant advances in controlling the spread of infectious disease were possible due to the development of vaccines during the twentieth century. Although the overall vaccination rates for the US population are approximately 90%, lower rates among subgroups (i.e., minorities, poor, elderly) continue to persist due to barriers to health care and lack of health information (Szilagyi et al., 2002). Community-based strategies that target these barriers and improve vaccination rates have become working models for vaccine programs, especially within the medically underserved areas in the US. More recently, preventive care (i.e., screening for cancer, hypertension, diabetes) has emerged as a leading public health issue. Studies examining the effect of promoting preventive care have shown that mortality rates due to cardiovascular disease and colon, prostate, and breast cancer have steadily decreased for most groups since the 1990s. However, these studies have also shown that females, the poor, and ethnic/racial minorities still experience higher rates of morbidity due to preventable chronic diseases (Lander et al., 2001; CDC National Office of Public Health Genomics, 2004; Chien et al., 2005; Chlebowski et al., 2005; Doty and Holmgren, 2005, Commonwealth Fund, 2006; Harrisetal.,2006; Blendon et al., 2007; Graham et al., 2007). These studies suggest that underlying societal, institutional, and economic factors continue to influence the persistence of health disparities even with increased public health strategies. Thus, it has become obvious that the issue of health disparities in the US is complex and multi-factorial for which there is no magic bullet solution. The role of individual genetic variability in response to common environmental stimuli has long been suspected as being a significant contributor to the prevalence of health disparities. Many in the biomedical research community had envisioned that the Human Genome Project would finally provide the tools to quantify the genetic contribution to health disparities. It was soon apparent that genetics explained only a fraction of disparities in chronic disease. However, the

4 14 R.G. Ramos and K. Olden Human Genome Project has helped biomedical researchers identify trends in functional genomic variability (i.e., gene protein interactions) among populations who experience greater disease morbidity and mortality (i.e., the disease phenotype). Often the inciting event for these disparate trends is the environmental exposure to one or more agents. An example of such is the exposure to cigarette smoking and asbestos. Individually, asbestos exposure and cigarette smoking confer a degree of risk for cancer development. However, together these environmental agents act synergistically to influence the resulting cancer phenotype (i.e., stage of invasiveness at diagnosis) (Liddell, 2001; Berry and Liddell, 2004). Additionally, if these exposures occur in an individual who is genetically predisposed to reduced bioavailability to detoxifying enzymes, such as cytochrome P-450 or glutathione-stransferase, the risk for cancer is significantly higher (Christiani, 2000). An emerging interest of molecular epidemiologists is the characterization of common, functional haplotypes among diseased individuals. Haplotypes are defined as a set of single nucleotide polymorphisms (SNPs) on a chromatid whose association is statistically significant (National Human Genome Research Institute, 2007). Thus, the identification of functional haplotypes among those who are experiencing greater morbidity due to a chronic disease would be invaluable. Furthermore, haplotype studies of various SNPs that demonstrate significant association with disease would provide further insight to explain disparities of disease severity. 2.3 Studying Gene Environment Interactions and Disease The current environment of risk-exposure assessments is one of great opportunity. Improving population health using newer and more powerful predictive models to quantify the cumulative contribution from multiple sources of risk (i.e., exposure, age, gender, genes) continue to be developed. The movement of modern biomedical research to a collaborative, multidisciplinary effort exemplifies the complexity of the genomic contribution to human health and disease. Table 2.1 lists some of the largest initiatives that will likely have an impact on global health in the near future. The National Institutes of Health (NIH) recently launched the Genetic Association Information Network (GAIN) which is a public-private partnership that will fund studies which aim to examine genome-wide associations in diseases such as depression, and certain autoimmune disorders (National Human Genome Research Institute, 2006). The Genes, Environment, and Health (GEI) Initiative is another NIH program that seeks to further our understanding of gene environment interactions by identifying new pathways of interaction and developing newer measurements of an individual s response to environmental stimuli including genomics, proteomics, and metabolomics (National Institutes of Health, 2007). Building on their prior successes with the Framingham Heart Study, the National Heart, Lung, and Blood Institute (NHLBI) of the NIH has retained 9,000 of the original Framingham Study participants and their family members for the Framingham

5 2 Gene Environment Interactions, Phenotypic Changes, and Human Health 15 Table 2.1 Summary of the largest gene by environment initiatives that will affect global public health Objective(s) Citations The NIH Long Life Family Study The NIH Road Map Initiative National Center for Toxicogenomics Chemical Effects in Biological Systems Knowledgebase (CEBS) The SNP Consortium 1. Identify characteristics of exceptional families that protect them from disease and disability, including lifestyle and genes 2. Identify positive factors that influence their longevity is also of interest 1. To identify major opportunities and gaps in biomedical research 2. Lays out a vision for a more efficient and productive system of medical research 3. Identifies the most compelling opportunities in three main areas: new pathways to discovery, research teams of the future, and re-engineering the clinical research enterprise To determine how disease may be influenced by environmental factors using bioinformatics combined with microarray-based strategies Integrates study design, clinical pathology, and histopathology data from all studies to enable discrimination of critical study factors Identified and mapped 1.5 million individual single nucleotide polymorphisms (SNPs) which are genetic markers (sequence landmarks in the genome) used to create genetic maps. These data have been made publicly available to researchers over the internet 1. In the genes: Searching for Methuselah. NIH Medline Plus Winter Live long? Die young? Answer isn t just in genes. New York Times, Aug. 31, 2006 The NIH roadmap. Science, Vol. 302, 3 Oct National Center for Toxicogenomics: An intoduction. Environmental Health Perspectives Vol. 111, No. 1T, Jan Systems toxicology and the chemical effects in biological systems (CEBS) knowledge Base. Environmental Health Perspectives Toxicogenomics, Vol. 111, IT, Jan The SNP consortium website: past, present and future. Nucleic Acids Research, Vol. 31, No. 1, pp , 2003

6 16 R.G. Ramos and K. Olden Table 2.1 (continued) Objective(s) Citations HapMap Project International Cancer Genome Consortium Aims to map the patterns of common SNP variation across the globe and to examine at combinations of SNPs that are inherited together, known as haplotypes The project aims to avoid duplication and waste by coordinating the cancer types studied and by establishing common standards of data collection and analysis NIH Cancer Genome Atlas Project Co-funded by the National Cancer Institute and the National Human Genome Research Institute, this project seeks to the prevention, diagnosis, and treatment of cancer through genome surveillance monitoring the genome for subtle changes that are suspected of contributing to cancer morbidity and mortality The NIEHS Sister Study A landmark study that seeks to untangle the link between the environment and breast cancer. This study envisions the enrollment of 50,000 female volunteers who have has a sister diagnosed with breast cancer A second generation human haplotype map of over 3.1 million SNPs. Nature, Vol. 449, pp , 2007 International consortium to tackle cancer genomes. Published online 30 April 2008, Nature, doi: /453015a NIH Institutes launch joint venture to map cancer genome. Journal of the National Cancer Institute, Vol. 98, No. 3, February 1, 2006 Sister study hopes to answer breast cancer questions. Environmental Health Perspectives, Vol. 109, No. 8, August 2001

7 2 Gene Environment Interactions, Phenotypic Changes, and Human Health 17 Genetic Research Study. This study aims to identify genes that may underlie diseases, such as heart disease and stroke, across three generations of family members (National Heart Lung and Blood Institute, 2006). Using the aforementioned model, genome-wide association studies are being planned using pooled DNA samples obtained from the cohorts of the NIH s Women s Health Study and the Women s Health Initiative. Twin studies have provided great insight to the familial or inherited contribution to disease development. In Finland, a landmark study of like- and opposite-sexed monozygotic (MZ) and dizygotic (DZ) twins has continued to examine the concordance and discordance of genetic traits with respect to cancer, obesity, osteoarthritis, asthma, and cardiovascular disease (Verkasalo et al., 1999; Lichtenstein et al., 2000). However, an exclusive genetic contribution to disease development in the study group (n > 3,000) has been less than 20%. Other twin studies have provided the evidence supporting the contribution of environmental factors, including the social and parental environment, to disease development among MZ and DZ twins such as depression and addiction disorders. More recently, it has been suggested that differential environmental exposures induce epigenetic changes in cells and this could be the mechanism that explains discordance for disease development among MZ twins (Poulsen et al., 2007). The contribution of race or ethnicity towards the development of environmentally-related disease has been studied extensively amongst Ashkenazi Jews (i.e., of medieval German origin). Such studies have found a disproportionately higher incidence of breast and ovarian cancer among this population when compared to other populations. One explanation for this trend is provided by a recent study that found a higher prevalence (8%) of abnormal breast cancer (BRCA 1) genes among Ashkenazi Jew females diagnosed with breast cancer (John et al., 2007). In the same study, the authors found a lower prevalence (2%) of this risk factor for breast and ovarian cancer among white Anglo females. However, most cancer studies that have sought a race-ethnic basis for cancer disparities have had contradictory results. Most of the contradiction is due to differential environmental exposures which are now recognized as powerful confounding factors. 2.4 The Environment, Genes, and Cancer The contribution of the environment to the incidence of cancer is not a new hypothesis. In fact, decades of epidemiological studies have revealed that risk conferred environmental factors is significant for 80 90% of newly-diagnosed cancers. However, many of these studies state that environmental exposures alone are not sufficient to incite the development of cancer. This suggests that an individual s genotype confers some degree of susceptibility to the ill-effects of environmental exposures such as tobacco smoke, alcohol use and exposure to industrial and agricultural chemicals. Additionally, the definition of environmental risk factors for cancer has expanded to include one s diet, the built environment and physical

8 18 R.G. Ramos and K. Olden activity. This section will discuss the current evidence for a gene environment interaction in the risk for diagnosis of cancer as well as the increased risk of death due to cancer. To ease the reading of the following section, a glossary of frequently used terms is provided in Table 2.2 and a list of candidate genes, including their abbreviations, and their functions, is provided in Table 2.3. A summary of the evidence presented in this section supporting the relationship between genes, environmental exposures and cancer is found in Table Bladder Cancer The National Cancer Institute (NCI) estimated that for the year 2008, there were 68,810 new cases of bladder cancer and an additional 14,100 lives lost (National Cancer Institute, 2007a). Gender disparities have been observed in the risk for bladder cancer among male smokers (OR = 7.1) when compared to female smokers (OR = 5.1). However, this disparity is reversed among non-smokers as the effect cumulative exposure to environmental tobacco smoke on bladder cancer incidence appears to affect more women than men (Anton-Culver et al., 1993). Studies have shown that although the frequency of bladder cancer diagnosis is 50% higher in Whites, the mortality rate among Whites and African-Americans is comparable (Prout et al., 2000). This suggests that bladder cancer in African-Americans is either diagnosed at a later stage of disease or this group is more susceptible to an aggressive form of this disease. The altered expression of carcinogen detoxifying genes (i.e., NAT2, GSTM1) and the DNA repair enzymes (i.e., NER enzymes) have been shown to confer an increased risk of bladder cancer. A 2006 study of the role NER genes plays in bladder cancer found that possessing one of the 22 SNPs that are found in seven NER genes significantly predicted the incidence of bladder cancer risk (p = 0.04) (Garcia-Closas et al., 2006). Further pair-wise association analysis found that the risk of bladder cancer increased fold when the variants were carried in both copies of four of the seven genes being studied. The risk of bladder cancer from the decreased production of enzymes responsible for detoxification or DNA repair is further increased among cigarette smokers. A gene environment interaction is biologically plausible since NAT2 and GSTM1 are responsible for detoxifying the cigarette-containing compounds, aromatic amines and polycyclic aromatic hydrocarbons. These compounds are also known to induce DNA damage. In 2005, a meta-analysis conducted by Garcia-Closas et al. found an increased risk of bladder cancer among smokers with SNPs in either NAT2 gene (p = 0.008) or the GSTM1 gene (p < ) (García-Closas et al., 2005). An examination by this same group of investigators found that the risk for bladder cancer among individuals with a SNP in one of the NER enzyme genes conferred a significant risk (p = 0.02) but SNPs in two genes conferred a much more substantial risk (p < 0.001) (Garcia-Closas et al., 2006). The distribution of the NAT2 and GSTM1 alleles has been estimated to be 40 and 50%, respectively, in the European and the US White populations (Vineis, 2004).

9 2 Gene Environment Interactions, Phenotypic Changes, and Human Health 19 Table 2.2 Glossary of terms used in this chapter Genotype Phenotype Bioavailability Healthy people Single nucleotide polymorphisms (SNPs) Haplotype Framingham heart study Women s Health Initiative (WHI) Odds ratio (OR) Oncogene Tumor suppressor gene (also known as anti-oncogene) The genetic constitution of an individual The observable properties of an organism that are produced by the interaction of the genotype and the environment The degree and rate at which a substance, such as an endogenous protein, is made available at the site of physiological activity A set of health objectives for the Nation to achieve over the prescribed decade. Healthy People 2010 outlined the objectives for the decade ; Healthy People 2020 will outline the objectives for the decade It can be used by many different people, States, communities, professional organizations, and others to help them develop programs to improve health Sites in the DNA sequence where individuals differ at a single DNA base Defined as a set of proximal single nucleotide polymorphisms (SNPs) on a chromatid that are inherited together in a block and whose association is statistically significant. The block of SNPs that characterize the haplotype are referred to as tag SNPs The objective of the Framingham Heart Study was to identify the common factors or characteristics that contribute to cardiovascular disease by following its development over a long period of time in a large group of participants who had not yet developed overt symptoms of CVD or suffered a heart attack or stroke. To date, the study has expanded to three generations of related participants is a long-term national health study that focuses on strategies for preventing heart disease, breast and colorectal cancer and fracture in postmenopausal women. This 15-year project involves over 161,000 women ages 50 79, and is one of the most definitive, far reaching programs of research on women s health ever undertaken in the US The unit of measure used to compare the presence of a risk factor for disease in a sample of diseased subjects vs. non diseased controls. An odds ratio = 1 indicates no risk; an odds ratio < 1 = a protective factor; an odds ratio > 1 = a risk factor. Additionally, the odds ratio is accompanied by a 95% confidence interval (i.e. that there is < a 5% likelihood that the risk is attributed to chance). When the confidence interval includes 1, the odds ration is considered not statistically significant A gene that normally directs cell growth. When mutated, an oncogene can promote and/or allow the uncontrolled growth of cancer. Mutations to oncogenes occur via environmental exposures or hereditary factors Responsible for producing the protein that controls cell growth. When mutated, aberrant cell growth and subsequently cancer, may occur. As with oncogene, mutations to tumor suppressor genes can occur via environmental exposures or hereditary factors

10 20 R.G. Ramos and K. Olden Table 2.3 Dictionary of genes cited in this chapter Gene Abbreviation Category Function Alcohol dehydrogenase ADH Detoxification of ethanol Aldehyde dehydrogenase ALDH Detoxification of ethanol ADH is a group of enzymes that function to metabolize ingested alcohols which could otherwise be toxic. The production of this enzyme is lower in females when compared to males and its genetic expression is higher among those of European ancestry when compared to those of Asian ancestry ALDH is a group of enzymes that function to metabolize aldehydes, the intermediate products of alcohol degradation Ataxia-telangiectasia ATM DNA repair ATM controls cell growth by coordinating DNA repair via activation of other proteins Breast cancer Type 1 or Type 2 BRCA1 Tumor suppressor gene BRCA genes participate in repairing cells with breaks in susceptibility gene BRCA2 double-stranded DNA Cell-cycle checkpoint kinase CHEK2 Cell cycle regulation CHEK2 is an enzyme is critical for cell cycle regulation via apoptosis and DNA repair via cell cycle arrest Phase 1 detoxification CYP450 enzymes are primarily tasked with the Phase 1 detoxification Cytochrome p450 CYP1A1 CYP1B1 CYP2E1 and biotransformation of xenobiotics. Specifically, CYP450 is a family of heme proteins tasked with the breakdown of exogenous substances (i.e., drugs and toxic compounds) as well as endogenous metabolic products (i.e., bilirubin, the breakdown product of hemoglobin) Epoxide hydrolase EPHX Phase 2 detoxification An enzyme that functions in detoxification during drug metabolism. Glypican 3 GPC3 Organ and tissue development This enzyme is critical in the conversion of intermediate metabolites (epoxides) to compounds that can be excreted from the body. These metabolites, which are generated as a result of cytochrome P450 break-down of aromatic compounds, are also mutagenic GPC 3 is an oncofetal protein. An oncofetal protein is one that is expressed during embryogenesis and is involved in organogenesis. The exact biological function of GPC3 is not known. However, GPC3 has been observed to be over-expressed in liver and skin cancer tumors

11 2 Gene Environment Interactions, Phenotypic Changes, and Human Health 21 Table 2.3 (continued) Gene Abbreviation Category Function Glutathione-S-transferase M, T, P variants Human epidermal growth factor receptor 2 GSTM1 GSTT1 GSTP1 Phase 2 detoxification GST enzymes play a critical role in the detoxification of various intermediate metabolites. These metabolites are often reactive inducing DNA damage and damage to DNA repair processes thus increasing the risk of carcinogenesis HER2/neu Growth factor HER2 is known to regulates cell growth and differentiation. The expression of HER2 on tumors is a critical for chemotherapy. Tumors that are negative for HER2 have poor response to chemotherapy Midkine MDK Growth factor Several cancers report an over-expression of MDK and is a pre-operative predictor of prognosis, including metastases. However, the exact mechanism by which it influences cancer prognosis is not known Myeloperoxidase MPO Phase 1 detoxification MPO plays a role in the metabolic activation of pro-carcinogens found Methylenetetrahydrofolate reductase MTHFR Conversion of ingested folic acid to bioactive form in cigarettes. Thus, differential expression of this enzyme has been hypothesized to influence the risk of lung cancer among smokers MTHFR catalyzes the bioconversion of folic acid or vitamin B9. This is significant since dietary sources of methyl donors (i.e., folic acid) are hypothesized to decrease the risk of cancers of the digestive system N-acetyl transferase NAT2 Phase 2 detoxification This family of enzymes facilitates the biotransformation of intermediate metabolites from Phase 1 detoxification via acetylation. These metabolites include polycyclic hydrocarbons that are found in cigarettes and cigarette smoke Nucleotide excision repair NER DNA repair NER enzymes are critical for DNA repair in damaged cells, specifically that which occurs as a result of oxidative damage

12 22 R.G. Ramos and K. Olden Table 2.3 (continued) Gene Abbreviation Category Function NAD(P)H:quinone acceptor xidoreductase NQO Phase 2 detoxification NQO enzymes are a family of enzymes that detoxify endogenous and exogenous substances via reduction of the intermediate metabolite, quinones, via electron reduction reactions. This enzymatic activity protects cells against oxidative stress; a risk factor for carcinogenesis Tumor protein 53 TP53 Cell cycle regulation This gene regulates the cell cycle via cell cycle arrest when damage to DNA occurs and if necessary, induction of apoptosis. Because of this function, it is often referred to as the guardian of the genome especially since it is a key player in the anti-cancer activities of many cells Progression elevated gene PEG10 Tumor progression The expression of this gene is elevated in the presence of DNA Phosphatase and tensin homolog deleted on chromosometen Thymidylate synthase TS Excision repair cross-complementing group 2 X-ray repair cross-complementing group V-raf murine sarcoma viral oncogene homolog B1 damage and during cancer cell progression. Its expression also correlates with genomic stability PTEN Tumor suppressor gene Cell cycle regulation via signaling to damaged cells to stop dividing and undergo apoptosis XDP (also known as ERCC2) DNA repair Transcription-coupled nucleotide excision repair XRCC DNA repair Base excision repair BRAF Oncogene A mutated form of the normal, cellular genes, known as proto-oncogenes, that contributes to the production of a cancer. Since they direct cell growth, the mutated oncogenes are hypothesized to increase the growth and spread of cancer cells

13 2 Gene Environment Interactions, Phenotypic Changes, and Human Health 23 Table 2.3 (continued) Gene Abbreviation Category Function Melanocortin-1-recpetor MC1R Production of melanin A key protein that regulates skin and hair color. It is found at the surface of cells that produce melanin called melanocytes. In the 1990s variants of the MC1R gene were found in 80% of humans who have red hair and fair skin. Individuals with skin cancer also have a higher frequency of mutations in this gene although the exact mechanism responsible remains unknown 8q24 Region (locus) on Polymorphisms in the region of this locus on chromosome 8 have been chromosome 8 shown to be significantly associated with prostate and breast cancer Insulin growth factor IGF1 Cell cycle regulation Through binding on various cells in various tissues, IGF stimulates cell growth and plays a critical role in anti-apoptotic activity Estrogen receptor beta ESR2 Nuclear receptor This protein plays a key role in DNA binding and subsequent gene transcription. It is normally expressed in the nucleus of normal epithelial and blood cells as well as their malignant counterparts Androgen receptor AR Nuclear receptor This protein plays a key role in DNA binding and subsequent gene transcription. Genes that are regulated by the androgen receptor are critical for the development and maintenance of the male sexual phenotype Serine peptidase inhibitor, Kazal type 1 SPINK1 Trypsin inhibitor Mutations of this protein are found to correlate with risk for acute and chronic pancreatitis

14 24 R.G. Ramos and K. Olden Table 2.4 Summary of the risk for cancer posed gene by environment interactions cited in this chapter Cancer Candidate gene(s) Environmental exposure(s) Phenotypic change due to interaction between genes and environment Bladder NAT2 GSTM1 NER Smoking confers higher risk in males Substantial increase in risk for smokers with SNPs in these genes Exposure to environmental tobacco smoke (ETS) confers higher risk for females Effect of ETS on those with SNPs not known Breast CYP1B1 Smoking increase in risk for breast cancer among smokers NAT2 2.5 increase in risk among smokers Colorectal CYP2E1 Frequent red meat or processed meat 2 3 increase in risk for rectal cancer among heavy meat eaters consumption XRCC Smoking 2.5 risk among ever-smokers XDP Alcohol consumption 2.9 risk among ever-drinkers Esophageal ADH ALDH Alcohol consumption 2 increase in risk amongst regular drinkers 2 risk among moderate drinkers 4.5 risk among heavy drinkers Leukemia CYP1A1 Chemicals CYP1A1 variants carriers: In-utero exposure to pesticides confers 5x increases risk of ALL; same exposure in childhood confers 3.6 increase in risk MTHFR TS CYP450 GST Diet Increased bioavailability of folate reduces risk for cancer Gene gene interactions among Phase I and Phase II enzyme genes (i.e., CYP450 and GST, respectively) with SNPs confer 2 10 risk for ALL

15 2 Gene Environment Interactions, Phenotypic Changes, and Human Health 25 Table 2.4 (continued) Cancer Candidate gene(s) Environmental exposure(s) Phenotypic change due to interaction between genes and environment Liver NAT2 Smoking Alcohol-related cirrhosis Lung CYP1A1 EPHX The risk for liver cancer increases 2 for smokers with liver disease (from OR = 1.23 to OR =2.67) GSTM1 Hepatitis infection Risk from null GSTM1 genotype doubles from OR = 1.18 to OR = 1.26 in HepA infected patients EPHX Heavy peanut butter consumption Risk from heterozygous EPHX genotype increases from OR = 2.75 to OR = 3.63 among those with heavy peanut butter consumption GSTM1 and GSTP1 MPO NAT2 Melanoma BRAF2 and BRAF 4 Mesothelioma GSTM1 NAT2 Pancreatic NQO1 GSTT1 Smoking Western lifestyle Environmental tobacco smoke Smoking 2 risk among light smokers (< 30 pack years) 7 risk among young Mexican Americans Male gender Exact risk still not known 2 risk among those with GSTM1 null genotype 4.5 risk among those with both GSTM1 null genotype and mutation in one or both GSTP1 alleles 0.25 reduction in risk for lung cancer 1.9 risk among smokers and non-smokers Asbestos-occupational exposure 1.9 risk among carriers of NAT2 fast-acetylator genotype 2.4 risk among carriers of BOTH NAT2 fast acetylator and GSTM1-null genotypes Smoking NQO1 levels were 6 greater GSTT-null genotype conferred a 5.0 increased risk among White female ever smokers and 3.2 risk among White male ever smokers Prostate GSTM Smoking 3.8 increased risk among smokers ( > 30 pack years) GSTP Diet rich in cruciferous vegetables Protective relationship has been established in-vitro NAT2 Smoking 2 risk among smokers

16 26 R.G. Ramos and K. Olden However, the global distribution of the NER genes is harder to quantify since they are numerous and have overlapping functions. Genome screening projects, such as the HapMap project, continue to identify the NER gene variants that confer the most risk individually or in tandem with SNPs of other detoxifying or DNA repair genes. The knowledge generated from studies, such as the HapMap project, will have a substantial impact on how human health risk assessments are conducted in the future Breast Cancer Breast cancer has long been a threat to women s health. In 2008, the NCI estimated that 182,460 women were be diagnosed with breast cancer and claimed the lives of 40,480 (National Cancer Institute, 2007b). In spite of this grim statistic, it is encouraging that both breast cancer incidence and mortality have shown a downward trend over the past 20 years. This is likely a result of improved public health outreach and communication strategies that seek to increase awareness of screening and knowledge of risk factors among women and their health care providers. As with other chronic diseases, higher rates of breast cancer mortality are observed for African-American females when compared to the national average (i.e., 33.5/100,000 and 25.0/100,000, respectively). Even more disturbing is the fact that this disparity exists even as the diagnostic rate of breast cancer is lower among African-American females (i.e., 117.5/100,000) when compared to national rate (i.e., 126.1/100,000) (Ries et al., 2008). Studies have shown that African-American women are less likely to be screened for breast cancer even though there is substantial evidence that this group suffers from a disproportionate burden of breast cancer mortality (Sassi et al., 2006). Additionally, they are more likely to be diagnosed with breast cancer that has progressed to a more advanced stage and is clinically characterized by poor prognostic markers (i.e., estrogen receptor-negative) (Chlebowski et al., 2005; Acharya et al., 2008). Environmental risk factors for breast cancer include lifestyle choices such as smoking, alcohol use, obesity, reduced or no physical activity, high-red meat diet, hormone replacement therapy, and parity (Mustacchi, 1961; MacMahon et al., 1970; Cerhan et al., 1998; Cho et al., 2006; Sillanpaa et al., 2007; Vona-Davis et al., 2007; Zhang et al., 2007). With respect to environmental exposures, animal studies conducted by the National Toxicology Program have found an association between exposure to 48 different chemicals and the development of mammary tumors (National Toxicology Program, 2007a). However, studies demonstrating a causal relationship between chemicals and breast cancer in humans have been contradictory. Additionally, identifying the critical periods of exposure to chemicals which are hypothesized to confer the greatest risks for cancer has been challenging. To date, the majority of the evidence associating chemical exposure to human breast cancer has been obtained from occupational studies (Brody and Rudel, 2003). A 2001 study by Davis et al. found that night shift workers of having an increased risk of breast cancer which has led to a suggested role for melatonin;

17 2 Gene Environment Interactions, Phenotypic Changes, and Human Health 27 the naturally-occurring hormone that serves as a critical antioxidant and provides protection against DNA damage (Davis et al., 2001; Schernhammer et al., 2001). Familial history of breast or any other type of cancer confers a risk for cancer diagnosis. Females who carry mutations in the BRCA1 and BRCA2 genes have a 20% increase in risk of developing breast cancer during their early 30s to 63% after age 70 (Claus et al., 1998). In this same study, by Claus 66% of BRCA mutation carriers reported a family history of breast cancer. However, it is estimated that 8 out of 9 women who develop breast cancer do not have an affected first-degree relative (Collaborative Group on Hormonal Factors in Breast Cancer, 2001). This suggests a potent role of the environment or gene environment interactions in the majority of breast cancer cases. The genotype of the breast cancer patient affects not only their susceptibility to environmental insults but their response to treatments. Genetic mutations in the PTEN gene have been shown to increase the risk of resistance to trastuzumab (i.e., Herceptin) therapy which counters the aberrant cell proliferation activity of the HER2/neu protein that is seen in 15 22% of early stage breast cancers (Berns et al., 2007). Assessments of mutations in the tumor suppressor gene, p53, are considered powerful prognostic markers for poor outcomes among node-negative breast cancer patients (Silvestrini et al., 1993). A 2007 study found that mutations in 2 different alleles of the cell-cycle checkpoint kinase (CHEK2) gene conferred an elevated risk of breast cancer (Bell et al., 2007). Among female breast cancer patients, the P85L variant was more frequent among African Americans and Ashkenazi Jews while the 1100delC was observed more frequently only among African Americans. Female relatives of patients with the disease ataxia-telangiectasia are often carriers of mutations in the ataxia-telangiectasia (ATM) gene (i.e., the gene responsible for the disease) and consequently are at significant risk for breast cancer before the age of 60 (OR = 2.9) and after (OR = 6.4) (Athma et al., 1996; Thompson et al., 2005). With respect to a gene-environment role in breast cancer, the NAT2, and cytochrome-p450 (CYP) genes each play a critical role in the production of enzymes necessary for detoxification of the compounds found in tobacco smoke and the metabolites of alcohol (Klaassen, 2001). Sillanpaa et al. found that among women smokers, the risk for breast cancer was increased by the presence of a SNP in the CYP1B1 gene or the combination of SNPs in both the NAT2 and CYP1A1 genes (Sillanpaa et al., 2007). In 2004, a study found that among Connecticut women exposed to environmental polychlorinated biphenyls (PCBs), a known endocrine disruptor, the risk for breast cancer was marginally increased (OR = 1.5) (Zhang et al., 2004). Additionally, Zhang et al. found that among women who were exposed to PCBs and who also possessed a specific SNP in the CYP1A1 gene m2 variant, the risk for breast cancer doubled (OR = 2.1) with the risk quadrupling (OR = 4.1) among post-menopausal women. This finding is significant since the CYP1A1 m2 variant is believed to be present in approximately 12% of the White female population. Studies such as these have a substantial public health impact since many endocrine disruptors are known to persist for long periods of time in the environment. This is complicated by the fact that the global distribution of the variant alleles in candidate genes for breast cancer is not yet known.

18 28 R.G. Ramos and K. Olden Colorectal Cancer Currently, death due to colorectal cancer is the third leading cause of cancer-related mortality in the Western world (National Cancer Institute, 2007c). The occurrence of this cancer before the age of 50 is about equal between men and women. However, after age 50 men become increasingly vulnerable. Colorectal cancer incidence and mortality has steadily decreased for most groups, except American Indians and Alaskan Natives, while rates among Whites and African Americans remain the highest. Recent studies have found significant variation among race and ethnic groups with respect to stage of diagnosis and risk for mortality (Chien et al., 2005; Alexander et al., 2007). The primary contributing factors to these disparities are patient education and access to preventive screening. The environmental risk factors for colorectal cancer are reflective of the Western lifestyle. These risk factors include diet, alcohol consumption, smoking, physical activity, and obesity. Moore et al. found that among subjects enrolled in the Framingham cohort, obesity defined by a BMI > 30 conferred a 1.5-fold risk among those years of age and 2.4-fold risk among subjects age (Moore et al., 2004). Additionally, the risk conferred by a high BMI was greater among males when compared to females. These authors also found that a large waist circumference (> 39 inches) conferred at least a 2-fold risk for colorectal cancer with the greatest risk observed among sedentary older and younger adults (relative risks = , respectively). More recently, Chia et al. found that an elevated serum level of the obesity biomarker, leptin, was associated with a 3.3-fold risk for colorectal among men (Chia et al., 2007). A 2005 multinational European cancer study found that both male and female who frequently consumed red meat were at an increased risk for colorectal cancer (OR = 1.35) with the risk increasing after the age of 50 (OR = 1.71) (Norat et al., 2005). Conversely, a diet rich in fish conferred a reduced risk of cancer before the age of 50 (OR = 0.69 vs. 1.5) and after the age of 50 (OR = 1.28 vs. 2.4). In a study among Finnish men years of age at baseline, heavy weekly consumption of alcohol (14 servings of beer or 16 servings of liquor) conferred a 3.5-fold lifetime risk for diagnosis of colorectal cancer (Toriola et al., 2008). A recent longitudinal study among adults years of age at baseline observed an inverse linear correlation between exercise frequency ( 5 times a week) and colon cancer (OR = 0.79) among (Howard et al., 2008) men. Additionally, men who were sedentary ( 9 h a day watching television or videos) were at a 1.6-fold increased risk for colon cancer. This risk is further increased by smoking status and affects not only the incidence but the aggressiveness of the tumor (Botteri et al., 2008). In addition to the evidence identifying elements of the Western lifestyle as independent risk factors for colorectal cancer, recent studies have found that this risk is further modified by an individual s genotype. The evidence supporting a role for the interaction between diet and SNPs in the CYP2E1 gene was published in 2002 (Le Marchand et al., 2002). The authors found that individuals who were carriers of a functional SNP in the CYP2E1 gene had a baseline elevated

19 2 Gene Environment Interactions, Phenotypic Changes, and Human Health 29 risk for developing rectal cancer. This risk was increased 2- to 3-fold among those who consumed a diet that was rich in either red meat or processed meats or ate pickled products. These findings are significant since the pro-carcinogenic N-nitrosamine compounds, which are found in both types of meats, are bioactivated by the CYP450 enzymes resulting in DNA adduct formation. Thus, it is biologically plausible that a SNP which results in an increased induction of these CYP450 enzymes accompanied by a diet rich in N-nitrosamine compounds would result in a significant risk of developing colorectal cancer. The evidence supporting the risk imposed by cigarette smoking and alcohol consumption suggests a significant role of SNPs in the DNA repair genes XRCC1 and XDP. In 2005, Stern et al. found that among patients diagnosed with colorectal cancer and functional SNPs in the XRCC1 genes, a history of ever smoking conferred a significant risk for colorectal cancer (OR = 2.9) (Stern et al., 2006). Additionally, among individuals with SNPs in the XDP gene, a statistically significant contribution (OR = 2.5) from alcohol consumption among ever drinkers when compared to never drinkers was observed. In an environment of robust cell cycle activity, such as the digestive system, there are many factors that contribute to the homeostasis that averts neoplastic growth. There is growing evidence of the role that methyl-donor nutrients (i.e., folic acid-containing foods) play in chemoprevention thus a diet that is rich in grains, fruits, and vegetables should be intuitive. Additionally, reduced intake of red meats and other foodstuffs which are known to induce the generation of DNA adducts or free radicals is currently advocated by public health professionals especially since the population distribution of functional SNPs in DNA repair genes is not yet known Esophageal Cancer Since the 1970s, the growth in the incidence and mortality rate of esophageal cancer has exceeded the annual growth rate of every other cancer (Brown and Devesa, 2002; Pickens and Orringer, 2003). In the US, the increase in the incidence of esophageal cancer has been greatest among White males but the mortality rates among African American males remains higher even though the diagnosis among this group has declined steadily over the last 15 years (Blot and McLaughlin, 1999; National Cancer Institute, 2007d). There has been some question about the contribution of improved diagnostics to the increase in esophageal cancer. However, a 2005 study found that when adjusted for the increased use of endoscopies, the incident rate and the primary site of diagnosis (the lower third of the esophagus) has remained steady since 1975 (Pohl and Welch, 2005). Risk factors for esophageal cancer include reflux disease (Barrett s esophagus), obesity, extremely low weight, and low fruit and vegetable consumption (Morris Brown et al., 1995; Engel et al., 2003; Samanic et al., 2006; Corley et al., 2008). More recently, the risk conferred role by alcohol consumption has come under greater scrutiny.

20 30 R.G. Ramos and K. Olden The association between esophageal cancer and alcohol consumption has been studied extensively in Japanese men (Miyazaki et al., 2002; Sakata et al., 2005; Ishikawa et al., 2006). It has been reported that heavy alcohol consumption and death due to alcohol-associated diseases has increased dramatically among Japanese males (Makimoto et al., 2000). Adding to the increased prevalence of this risk factor is the identification of SNPs, amongst Japanese men, in the genes encoding for two enzymes that are critical for detoxifying ethanol; alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) (Tanaka et al., 1996, 1997). Researchers have examined the association between the polymorphisms in the ADH and ALDH genes among Eastern Asian men and the risk of being diagnosed with esophageal cancer (Yang et al., 2005; Chen et al., 2006). Yang et al. found an increased risk of esophageal cancer among Japanese men who possessed an ALDH polymorphism and were either moderate drinkers (OR = 1.88) or heavy drinkers (OR = 4.62). Chen et al. also found that the risk of esophageal cancer was further modified by the lifetime drinking (i.e., > cc. of beer for 20 consecutive years) resulting in a 20-fold increase among those with an ADH gene polymorphism and 30-fold increase among those with an ALDH gene polymorphism. Although the majority of gene environment interaction studies, with respect to esophageal cancer, have been conducted among frequent/heavy drinkers (i.e., 2 six packs of beer/day), the risk conferred from a susceptible genotypes among other categories of drinkers is not known. These include binge-drinkers, younger vs. older drinkers and those who drink alcoholic beverages with higher alcohol content (i.e., 12% ethanol in hard liquor vs. 5% ethanol in beer). Furthermore, the degree of penetrance or the population distribution of the candidate genes for esophageal cancer remains unknown. Such information could have a dramatic effect population health since the 5-year survival rate of this cancer is 20 25% Leukemia Leukemia is a cancer that originates in the bone marrow and results in a large number of blood cells to be produced. Although this cancer occurs more often in adults than in children (10 to 1), is the most common pediatric cancer and is the leading cause of mortality among children < 14 years of age. This cancer is most likely to be diagnosed in White males although the mortality rates between Whites and African-Americans are comparable. Leukemia is also divided into four types; acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML). ALL is the most common type of leukemia in children while AML, primarily found in older adults, is the most common among adults. Epidemiologic surveillance studies have reported geographic variation in the incidence of leukemia (i.e., higher incidence in wealthier, developed countries) but the identification of population-attributable factors is lacking.